The adapter type protein CMS/CD2AP binds to the proto-oncogenic protein c-Cbl through a tyrosine phosphorylation-regulated Src homology 3 domain interaction
The adapter type protein CMS/CD2AP binds to the proto-oncogenic protein c-Cbl through a tyrosine phosphorylation-regulated Src homology 3 domain interaction
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DOI：
10.1074/jbc.m005784200
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发表时间：
2001-02-16
影响因子：
4.8
通讯作者：
Hanafusa, H
中科院分区：
文献类型：
--
作者：
Kirsch, KH;Georgescu, MM;Hanafusa, H
CMS/CD 2AP是一种细胞质蛋白，对肾小球滤过和T细胞功能的完整性至关重要。CMS包含结构域和图案特征的蛋白质-蛋白质相互作用，它是参与调节肌动蛋白细胞骨架，我们在这里报告的个人SH 3结构域CMS结合到磷酸酪氨酸蛋白的类似80，90，和180 kDa的细胞裂解物刺激表皮生长因子。CMS的第二个SH 3结构域特异性地结合到120 kDa的酪氨酸磷酸化蛋白，我们将其鉴定为原癌蛋白c-Cbl。CMS的c-Cbl结合位点映射到c-Cbl的羧基末端，并且不同于已知结合含SH 3蛋白的富含脯氨酸的区域。CMS与c-Cbl的结合在酪氨酸磷酸化缺陷的c-Cbl突变体中显着减弱，表明这种相互作用依赖于CMS的酪氨酸磷酸化。这也意味着CMS与c-Cbl相互作用的诱导方式后，刺激的各种细胞表面受体。免疫荧光分析表明，这两种蛋白质共定位在板状伪足和细胞的前缘，我们建议CMS与c-Cbl的相互作用提供了一种机制，c-Cbl协会和调节肌动蛋白细胞骨架。
CMS/CD2AP is a cytoplasmic protein critical for the integrity of the kidney glomerular filtration and the T cell function. CMS contains domains and motifs characteristic for protein-protein interactions, and it is involved in the regulation of the actin cytoskeleton, We report here that the individual SH3 domains of CMS bind to phosphotyrosine proteins of similar to 80, 90, and 180 kDa in cell lysates stimulated with epidermal growth factor. The second SH3 domain of CMS bound specifically to a tyrosine-phosphorylated protein of 120 kDa, which we identified as the proto-oncoprotein c-Cbl. The c-Cbl-binding site for CMS mapped to the carboxyl terminus of c-Cbl and is different from the proline-rich region known to bind SH3-containing proteins. CMS binding to c-Cbl was markedly attenuated in a tyrosine phosphorylation-defective c-Cbl mutant indicating that this interaction is dependent on the tyrosine phosphorylation of CMS. It also implies that CMS interacts with c-Cbl in an inducible fashion upon stimulation of a variety of cell-surface receptors. Immunofluorescence analysis revealed that both proteins colocalize at lamellipodia and leading edges of cells, and we propose that the interaction of CMS with c-Cbl offers a mechanism by which c-Cbl associates and regulates the actin cytoskeleton.